Download Comparison of Uhl`s anomaly, right ventricular outflow tract

Review Article
Indian J Med Res 131, January 2010, pp 35-45
Comparison of Uhl’s anomaly, right ventricular outflow tract
ventricular tachycardia (RVOT VT) & arrhythmogenic right
ventricular dysplasia/cardiomyopathy (ARVD/C) with an insight into genetics of ARVD/C
Pranathi R. Pamuru, Maithili V.N. Dokuparthi, Sushant Remersu*, Narasimhan Calambur** & Pratibha Nallari
Department of Genetics, Osmania University, Hyderabad, *Kakatiya Medical College, Warangal &
**
Cardiology Care Hospital, The Institute of Medical Sciences, Hyderabad, India
Received November 27, 2008
Among the right ventricular conditions, Uhl’s anomaly, arrhythmogenic right ventricular dysplasia /
cardiomyopathy (ARVD/C) and right ventricular outflow tract ventricular tachycardia (RVOT VT) are
disorders that exhibit pathogenic changes involving the right ventricular (RV) myocardium, and are
expected to be severe or milder forms of the same condition. The review focuses on the aspect whether
the three RV disorders are a spectrum of the same disease. ARVD/C is the only condition among
these to be genetically well characterized. Also, variations in the clinical expression of ARVD/C due
to the genetic heterogeneity are examined. Based on clinical manifestations, age at onset, gender ratio
and the possible molecular mechanisms implicated, Uhl’s anomaly, ARVD/C and RVOT VT may be
considered as separate entities. Further, to differentiate between the three RV disorders, the molecular
studies on ARVD/C might be helpful. An attempt was made to differentiate between the eleven different
types of ARVD/Cs based on clinical symptoms presented including the progression of the disease to
the left ventricle, ventricular arrhythmias and clinical characteristics like ECG, SAECG, ECHO and
histopathological studies.
Key words ARVD/C - genetic heterogeneity - RVOT VT - Uhl’s anomaly
may be milder or severe manifestations of the same
condition.
Introduction
Uhl’s anomaly, arrhythmogenic right ventricular
dysplasia / cardiomyopathy (ARVD/C) and right
ventricular outflow tract ventricular tachycardia
(RVOT VT) involve pathogenic changes in the right
ventricular (RV) myocardium. Though complete
pathogenic mechanisms have not been discovered for
the three disorders, there is a speculation that these
In 1952, Uhl described a case in which the wall
of the right ventricle was said to be paper thin and
almost devoid of muscle fibres, an appearance akin to
parchment heart1. Fontaine et al2 described an entity,
called arrhythmogenic right ventricular dysplasia,
which was characterized, by localized deficiency
35
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INDIAN J MED RES, january 2010
or fibrofatty tissue replacement of right ventricular
myocardium. Since then, the term ARVD/C has been
used increasingly and references to the Uhl’s anomaly
have decreased raising the question whether the two
conditions are different entities or are variants of a
single underlying disorder3. Further cases with the
morphology of ARVD/C have been inaccurately
classified as Uhl’s anomaly4-24. Hence, it became
necessary to differentiate between the two conditions.
Right ventricular tachycardia is commonly due
to ARVD/C or idiopathic right ventricular ventricular
outflow tract (RVOT) ventricular tachycardia (VT)25,26.
ARVD/C is an inherited cardiomyopathy with right
ventricular dysfunction due to fibrofatty replacement
of myocardium, predisposing to ventricular tachycardia
and death. RVOT VT is a benign condition, considered
as a primary electrical disorder in the absence of
structural heart disease27. Frequency of symptoms
and history of syncope are similar in ARVD/C and
RVOT VT25,28. Detailed analyses using MRI, SAECG
and endomyocardial biopsy have detected structural
abnormalities in patients with RVOT VT were similar to
those seen in the early stages of ARVD/C25,29-33. Hence,
to know whether the two conditions represent separate
entities or together form a continuous spectrum of a
disease is clinically important for better prognosis and
management.
Uhl’s anomaly and RVOT VT, severe and mild
forms of ARVD/C?
ARVD/C and Uhl’s anomaly are considered as
different manifestations of the same disease34. In
Uhl’s anomaly, there is virtually complete absence
of the myocardium of the parietal wall of the right
ventricle and the parietal wall is composed of the
opposing endocardial and epicardial ventricular
surfaces, with no fatty tissue interposed between these
layers. These changes are congenital and diagnosed by
foetal echocardiography35. ARVD/C is characterized
by patchy and localized replacement of the parietal
wall of the right ventricle by fibrofatty tissue. This
adipose replacement occurs primarily within the
ventricular outflow tract, inlet or apical regions,
sometimes progressing to the left ventricle. The clinical
presentation of Uhl’s anomaly includes cyanosis,
dyspnoea and right-sided failure while patients with
ARVD/C exhibit ventricular arrhythmias that may
range from asymptomatic ventricular complexes to
ventricular fibrillation. Uhl’s malformation is usually
diagnosed in neonatal or infant life, while ARVD/C
patients manifest symptoms during adolescence. In a
study, the male: female ratios for Uhl’s anomaly was
found to be 1.27:1, while for ARVD/C it was 2.28:1,
this difference in the degree of male predominance
was considered significant3. Uhl’s anomaly has been
associated with other disorders like dysplasia of the
tricuspid valve, pulmonary atresia and persistent ductus
arteriosus, while ARVD/C has been seen as a part of a
syndrome with hair and skin abnormalities inherited in
an autosomal recessive form or as an isolated condition
which is inherited in an autosomal dominant fashion.
James36 suggested that both conditions share a
common pathogenesis of apoptotic dysplasia. In Uhl’s
anomaly the apoptotic process may be incessant and
starts early in infancy or childhood with complete
destruction of RV wall, whereas in ARVD/C there
may be episodic apoptosis beginning in adolescence36.
Though the pathogenic mechanism in ARVD/C
is not completely understood, it is believed that
defects in desmosomal components, which provide
mechanical coupling between the intermediate
filaments and the cytoplasmic membranes of adjacent
cells, may compromise its adhesive function, predisposing to myocyte detachment and death. Further,
as the regenerative capacity of myocardium is
limited, fibrofatty substitution is observed as repair
mechanism37.
Gras et al38 showed that the suppression of the
signaling of canonical Wnt / β-catenin pathway could
be the pathogenic mechanism underlying ARVD/C. The
probable molecular mechanism hypothesized was that
by mutating desmosomal protein impairs desmosomal
assembly releasing free plakoglobin from the
desmosomes, which could translocate into the nucleus
and through competition with β-catenin suppress
signaling through the canonical Wnt/ β -catenin–Tcf/
Lef pathway. Suppression of Wnt/ β -catenin signaling
provokes adipogenesis, fibrogenesis, and apoptosis, the
characteristic hallmark of ARVD/C38. The mechanism
involved in Uhl’s anomaly would probably involve the
factors that would either trigger apoptotic pathways
or fail to protect from apoptosis leading to complete
loss of right ventricular myocardium. Wnt pathway
has not been implicated in Uhls anomaly till date but
apoptosis can be triggered by many factors including
the components of the Wnt pathway.
In the canonical Wnt pathway, frizzled receptors
signal to the dishevelled (Dsh) protein, which
causes accumulation of cytoplasmic β-catenin. After
Pamuru et al: Comparison of three right ventricular cardiomyopathies
translocation to the nucleus, β-catenin activates T
cell factor (TCF)-dependent target genes. Human
frizzled receptor hFz5 induces apoptosis and the Cterminal region of the cytoplasmic tail of hFz5 shares
significant similarity with the corresponding region
of Xfz8a (frizzled receptor in Xenopus), required for
JNK (a family of stress-activated serine/threonine
kinases) activation and apoptosis. Wnt ligand Xwnt5a
is a negative regulator of apoptosis induced by Xfz8.
A similar process might be expected in Uhl’s anomaly
where the Wnt ligands fail to suppress the apoptosis
leading to complete loss of RV myocardium. Studies
in this regard are required to implicate or rule out this
pathway in Uhl’s anomaly39.
Mallat et al40 showed that apoptosis could be the
primary process that precedes fibrofatty replacement of
myocardial tissue in ARVD/C unlike in Uhl’s anomaly
where the only process of apoptosis is reported.
The mechanism operating in ARVD/C should be
essentially different from the apoptosis triggered in Uhl’s
anomaly as in the later condition there is complete loss of
RV myocardium unlike in ARVD/C where it is assumed
that apoptosis process not being continued incessantly
but being only episodic both spatially and temporally and
result in the focal loss of myocardium in a few limited
regions or may be more diffused. Further, there is no
fibrofatty replacement of myocytes observed in Uhl’s
anomaly in contrast, which is the main pathological
feature observed in ARVD/C. The difference in clinical
expressions and the probable pathogenic mechanisms
in these two conditions indicate that Uhl’s anomaly and
ARVD/C may be separate entities.
37
In right ventricular outflow tract (RVOT) ventricular
tachycardia (VT), which occurs predominantly in
young adults, the origin of VT in RVOT tachycardia
is usually in the septum, while for ARVD/C it is in the
parietal wall. Kinoshita et al41 reported mild fibrosis
and fatty infiltration in 8 of the 12 patients with RVOT
VT. In the 12 lead ECG, the mean QRS duration is
longer in ARVD/C patients compared to RVOT VT
in all the leads41. Late potentials on signal averaged
electrocardiogram were not present in RVOT VT
patients but were present in 78 per cent of the patients
with ARVD/C. Unlike ARVD/C patients, none of the
RVOT tachycardia patients had structural abnormalities
on echocardiography or angiography, further no major
structural abnormalities were observed in RVOT VT
patients in MRI27. Follow up of patients with RVOT
VT has shown that they do not appear to progress to
ARVD/C but RVOT VT was reported as a localized
form of ARVD/C in 50 per cent of cases investigated42.
Table I shows differences in the clinical expressions of
the RVOT VT and ARVD/C. These studies indicate that
RVOT VT could be a different entity and not a milder
form of ARVD/C and that RVOT VT does not progress
into ARVD/C during a period of time. But to identify
and distinguish between milder form of ARVD/C and
RVOT VT is difficult as there is no technique to either
establish or rule out these conditions. As the genetic
basis of ARVD/C has been established, milder form
of ARVD/C can be identified by screening the family
members in the familial cases and the sporadic cases
can be distinguished by molecular studies.
The molecular pathology of the disorders affecting
the right ventricle has not been identified. The basis of
Table I. Clinical expressions of the RVOT VT and ARVD/C
Age at onset
Sex
Family history
Reports of SCD
12 lead ECG
SAECG
ECHO
Arrhythmias
RVOT VT
Third or fifth decade of life
Females predominantly
Normal
ARVD/C
Third or fourth decade of life
Males predominantly
+
+
-T wave inversion in precodial leads from V1 - V5
- Prolongation of QRS complex in leads V1 or V2
- ε waves observed
Late potentials observed
Structural and wall motion abnormalities of RV
PVCs, SVT, NSVT, VF
Normal
Normal
PVCs, repetitive monomorphic VT, induced / sustained VT
Septum
Parietal wall
Origin of arrhythmia
Mechanism of arrhythmia
cAMP mediated triggered activity Reentrant mechanism
Normal
Increased
BNP levels
SCD, sudden cardiac death; ECG, electrocardiogram; SA ECG, signal averaged ECG; ECHO, echocardiography; BNP, brain natriuretic
peptide; PVC, polymorphic ventricular complex; SVT, sustained ventricular tachycardiac; NSVT, non sustained VT; VF, ventricular
fibrillation
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INDIAN J MED RES, january 2010
preferential affection of right ventricle in the setting of
the right ventricular disorders is the difference between
the right and left ventricular wall thickness and their
adaptation to the pressure of the blood flow against
which the myocardium has to pump. Therefore, the left
ventricle is thick-walled in order to counter the high
pressure of the blood flow while the right ventricle also
needs to adapt to the wide variations of the preload, i.e.
the volume of blood it needs to accommodate, due to
which the thin-walled right ventricle is highly distended.
Among these three right ventricular disorders, ARVD/
C is the only condition genetically well characterized.
The molecular studies would aid in recognizing the
condition in the early stages and the asymptomatic
family members. It would also help in distinguishing
the different types of RV disorders.
Genetics:
Eleven autosomal dominant forms of ARVD/C, all
exhibiting incomplete penetrance have been identified.
Naxos disease, associated with palmoplantar keratosis
and wooly hair, has been identified as a recessive
condition. Since, the identification of the first locus for
ARVD/C in 1994, eight genes have been identified so
far43. The list of the genes identified for ARVD/Cs and
their clinical manifestations is shown in Table II.
Non-desmosomal genes identified:
Transforming growth factor-beta 3 (TGF-β3): Mutations
in untranslated 5’ and 3’ regions of TGF-β3 gene have
been identified in the causation of ARVD/C-1. TGF-β3
induces a fibrotic response in various tissues in vivo44
and modulate expression of genes encoding desmosomal
proteins in different cell types. Experiments have shown
that incubation of cardiac fibroblasts in presence or
absence of exogenous TGFβ3 revealed increased
expression of plakoglobin gene45 and overexpression of
TGFβ3, caused by UTR mutations which might affect
cell-to-cell junction stability leading to a final outcome
as observed in ARVD/C which is caused by mutations in
desmosomal genes.
Cardiac ryanodine receptor gene (RyR-2): RyR-2
is the first gene identified for the condition, which
is chararcterized by the presence of peculiar effortinduced ventricular arrhythmias and high penetrance46.
This unique form of the condition was named ARVD/
C-2. Mutations in RyR-2 gene decrease the binding
strength between RyR2–FKBP12.6 and increase the
open probability of the channels enhancing Ca2+ leakage
from the sarcoplasmic reticulum. In turn, the increased
cytosolic Ca2+ concentration would impair excitation-
contraction (E-C) coupling giving rise to arrhythmias
and induce Ca2+ activated apoptosis/necrosis processes,
leading to myocardial damages46 as reported in ARVD/
C patients.
Transmembrane protein 43 (TMEM43): TMEM43 is
the recently identified gene for ARVD/C-547. Signaling
pathways have been implicated in pathogenesis of
ARVD/C. For example, plakoglobin, when freed from
desmosomal complexes, translocates to the nucleus
where it competes and opposes the action of β-catenin
and downregulates the canonical Wnt/-β-catenin
signaling pathway. Suppression of the canonical
Wnt/ β-catenin signaling upregulates two adipogenic
transcription
factors,
CCAAT-enhancer-binding
protein-α (C/EBP-α) and peroxisome proliferator
response elements (PPARγ)38. A genome-wide scan
for PPREs identified 1085 potential target genes of
PPARγ, including TMEM4347. If TMEM43 is a part
of an adipogenic pathway regulated by PPARγ, then
perhaps dysregulation of this pathway may explain the
fibrofatty replacement of the myocardium observed in
ARVC patients47.
Desmosomal genes identified:
Desmosomes are major intercellular adhesive
junctions found in all epithelial and cardiac tissues.
They provide anchorage of the plasma membrane to the
cytoskeleton by interacting with intermediate filaments
on their cytoplasmic side, thus contributing to tissue
integrity. Desmosomes consist of three major protein
families- Cadherins (desmogleins and desmocollins),
Armadillo (Arm) repeat proteins (plakoglobin and
plakophilins) and plakin (desmoplakin).
Desmoplakin: Mutations in the desmoplakin gene
have been identified in the causation of ARVD/C-8
and arrhythmogenic left ventricular cardiomyopathy
(ALVC)48,49. Mutations at the inner dense plaque,
particularly affecting the desmin-binding site of
desmoplakin may result in ARVD/C with predominantly
left ventricular involvement and clinical overlapping
with dilated cardiomyopathy, while the mutations
affecting the outer dense plaque of desmosome
(desmoglein2, plakoglobin, plakophilin2 and the Nterminal of desmoplakin) result in ARVD/C with the
ordinary described phenotype indicating that mutations
in the same gene at different locations might lead to
different phenotypes either ARVD/C or ALVC50.
A variant of ARVD/C, where the condition is
localized to left ventricle (LV), is called arrhythmogenic
left ventricular cardiomyopathy (ALVC). The glaring
+
- Trabecular
disarrangement and RV
dyskinesia at apex
- Moderate
- LV involved with
localized motion
abnormality
SAECG
ECHO
Not fulfilled
- Extensive replacement - Myocardial atrophy
type fibrous and fatty
with transmural
Infiltration
fibrofatty tissue
- Surviving myocytes
replacement in the
entrapped within fibrous walls of both RV and
and fatty tissue
LV
- Myocytosis and
lymphocytic
inflammatory
infiltrates
Biopsy/Autopsy
Diagnostic
criteria
+
Family history
Not fulfilled
+
RV and LV
Only RV, no LV
involvement reported
Structural
progression
+
Not fulfilled
- Infiltration of RV by
fat with presence of
surviving strands of
cardiomyocytes
+
RV and LV,
predominantly RV
+
- RV enlargement with
poor systolic function
- Minor and localized
motion abnormalities
- Aneurismal segment in
RVOT
- RV kinetic alteration
- RV severely dilated
with trabecular
disarrangement
regional wall with
kinetic abnormalities
both diffuse and
localized
not known
+
+
RBBB
dilation of RV
- T-wave inversion in
- T wave inversion from - T wave inversion
V1-V5
precordial leads V1 - V4
- Prolongation of QRS
- Prolongation of QRS in
V1, V2 or V3
- incomplete RBBB
- ST elevation
- QTS dispersion
- ε waves
SVT, NSVT, PVC and
VF
Plakophilin-2
ECG
SVT, NSVT, PVC and
VF
NSVA
Ventricul
Arrhythmias
Desmoplakin
TGFβ-3
Gene
NSVT with LBBB
morphology
Desmocollin-2
not known
Not fulfilled
- Myocardial atrophy
with replacement type
- Fibrosis and mild
infiltration
+
RV and LV
+
Not fulfilled
Extensive fibrofatty
replacement of RV
myocardium
+
RV and LV,
predominantly LV
not known
- RV kinetic abnormality - Severely dilated
hypokinetic RV with
- LV involvement
with LV kinetic
diastolic bulging and
disarrangement
abnormalities both
diffuse
+
- T wave inversion from - T wave inversion
V1-V5
from V1 -V6
- PQ Prolongation
- ε waves
- Low voltages of QRS
- Complete RBBB
- ε waves
SVT, NSVT, PVC and
VF
Desmoglein-2
Table II. Genes involved in different types of ARVD/Cs and their clinical manifestations
Fulfilled
- Fibrofatty infiltration
of RV and LV
myocardium
-Surviving myocytes
surrounded by
fibrosis embedded
fatty tissue
-
Biventricular
involvement
+
- Mild to severe RV
dilation
- Regional/ diffuse
hypokinesia
- LV abnormalities
not known
- T wave inversion
from V1-V3
- Prolonagtion of QRS
- complete/ incomplete
RBBB
- ε waves
SVT
Plakoglobin
Pamuru et al: Comparison of three right ventricular cardiomyopathies
39
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INDIAN J MED RES, january 2010
departure from ARVD/C is apparent exclusive left
sided nature of the disease51. Suzuki et al52 reported
a 43 year old man, who initially presented with left
sided cardiomyopathy with preserved RV contraction,
10 years later developed biventricular progression.
Table III gives the clinical findings of ARVD/C and
ALVC. The clinical presentations of ALVC are similar
to ARVD/C except that the disease is restricted to LV
with a normal RV.
followed by an extracellular anchor domain (EA);
a single transmembrane domain; and a cytoplasmic
domain anchoring the cytoskeleton, an essential process
for cell adhesion. So far all the mutations reported in
this region have been observed in the highly conserved
domains of DSG-2 and it is possible that even a single
amino acid change could result in differences in
molecular affinity and possibly in the abolition of the
adhesive capacity of cadherins.
Plakophilin-2 (PKP-2): Highest number of mutations
have been reported in PKP-2 gene causing ARVD/C9 thus suggesting the plakophillin may be a frequent
cause of the disease. Plakophillin-2 is an essential
armadillo-repeat protein of the cardiac desmosome.
Plakophilins together with other desmosomal proteins,
assemble to form cell adhesion complexes, which
carry out important functions such as mechanically
safeguarding cellular and organ architecture, and
participating in signal transduction pathways53.
Desmocollin-2 (DSC-2): As desmocollin-2 (DSC-2) is
also a component of demosomal complex, screening of
this gene was initiated and mutations were identified
causing ARVD/C-11. DSC-2 plays a crucial role in cell
adhesion and tissue morphogenesis, it is speculated
that absence of DSC-2 or incorporation of mutant
DSC-2 in desmosomes would result in structurally and
functionally impaired desmosomes. This corroborates
with the widely accepted “desmosomal model”
hypothesis55, according to which under conditions
of mechanical stress, impaired desmosome function
due to desmsosmal gene mutations would lead to
detachment and death of cardiac myocytes followed by
inflammation and fibrofatty replacement37.
Desmoglein-2 (DSG-2): DSG-2 is expressed in cardiac
tissue and is an important component of desmosomal
complex. Screening of this gene identified mutations
accounting for ARVD/C and as this is the tenth loci for
the condition was named ARVD/C-1054.
Desmosomes consist of 2 desmosomal-specific
cadherin family members desmogleins (DSGs) and
desmocollins (DSCs). All cadherins have tripartite
functional domains - a calcium-inducible, extracellular
amino terminal domain, important for homophilic
intercellular associations, with 4 domains (EC1 to EC4),
Plakoglobin: Earlier mutations in plakoglobin were
reported in a variant of ARVC called Naxos disease,
which is characterized by signature features of
ARVC accompanied by diffuse non-epidermolytic
palmoplantar keratoderma (NEPPK) and wooly hair
(WH)56, a recently identified novel autosomal dominant
plakoglobin mutation without any cutaneous and hair
Table III. Clinical findings of ARVD/C and ALVC
ARVD/C
ALVC
ECG
- Negative T-waves in precordial leads
- QRS prolongation in V1, V2 or V3
- Incomplete RBBB
- ST segment elevated
- Low QRS voltages in peripheral leads
- QRS dispersion (> 20 ms)
- Presence of ε waves
- Inverted T waves in inferior and lateral leads
- Abnormal Q waves in the leads V5, V6, I and aVL,
left axis deviation
- PVCs of LBBB pattern
SAECG
Late potentials observed
Late potentials observed
Ventricular arrhythmias
VF, SVT, NSVT, PVCs
VF, SVT, NSVT, PVCs
ECHO
- Mild to severe RVdilation with kinetic abnormality
- LV dilation
- LV involvement with kinetic Abnormality both
diffuse and localized
- Diffuse and severe hypokinesis of the LV with no
abnormalities of the RV
RV dilation with extensive replacement type fibrosis
and fatty infiltration
LV dilation with focal areas of fibrosis and fatty
infiltration
Biopsy/Autopsy
ECG, electrocardiography; LBBB, left bundle branch block; VF, ventricular fibrillation; SVT, sustained ventricular tachycardia; NSVT,
non-sustained ventricular tachycardia; PVCs, poly ventricular complexes
Pamuru et al: Comparison of three right ventricular cardiomyopathies
abnormalities. Plakoglobin is also known to participate
in Wnt-signaling pathways, where it is associated with
Tcf/Lef transcription factors57 and regulates functions
such as cell proliferation and apoptosis58. Different
mechanisms leading to altered turnover kinetics of
plakoglobin might be responsible for the two variants
- Naxos disease with skin and hair abnormalities and
dominant ARVC form.
Clinical pathology:
ARVD/C may manifest in the following clinical
phases: concealed, overt, right ventricular failure or
biventricular failure pump phase. In the early concealed
phase, individuals are often asymptomatic but may be at
a risk of sudden cardiac death, notably during extreme
exertion. Structural changes are absent or subtle and
are frequently confined to one region of the triangle
of dysplasia: the inflow, outflow, and apical portions
of the RV. The second phase marks the onset of the
overt electrical disorder, with symptomatic arrhythmia
of RV origin and more prominent RV morphological
abnormalities readily discernible by conventional
imaging. In the third phase, diffuse RV disease results
in an isolated right heart failure. LV involvement with
biventricular pump failure occur in the final stage,
leading to a phenotype that may resemble dilated
cardiomyopathy59.
Initial symptoms:
The first clinical presentation could be sustained
ventricular tachycardia, palpitation, syncope, chest
pain, recurrent ventricular tachycardia or cardiac arrest
due to ventricular fibrillation. Clinically ARVD/C is
responsible for approximately 5 per cent of unexplained
sudden cardiac death (SCD) cases in young athletes in
United States and 27 per cent of such cases in Italy60-62.
Cardiac deaths in ARVD/C are accounted by sudden
death and heart failure. Hulot et al63 reported heart
failure as the cause of death in about two-thirds of the
patients investigated.
Angiotensin
converting
enzyme
(ACE)
polymorphism was analyzed in ARVD/C patients
and a high prevalence of DD genotype in patients
with syncope was observed and might be useful in
identifying high-risk patients for syncope64.
The clinical manifestations of the probands
harbouring desmoplakin gene mutations are similar to
patients with other ARVCs except that probands with
DSP mutations are characterized by a high occurrence
of sudden death even in the concealed phase49, while
41
individuals harbouring plakophilin-2 genes mutations
express the disease earlier in life, as determined by
age at first clinical manifestation and age at first
arrhythmias65.
Structural progression of the condition:
Biventricular involvement is expected as the
disease progresses. Involvement of the RV or LV
is dependant on the site of the mutation in patients
carrying desmoplakin gene mutation. Mutations in
the plakophilin-2 genes cause the disease affecting
predominantly the RV, while desmocollin-2 gene
mutations may be more frequently associated with
left ventricular phenotype without significant right
ventricular involvement55. LV involvement is not
observed in patients with TGF β-3 gene mutation.
Diagnosis:
A Task Force of the European Society of Cardiology
has proposed the criteria for the clinical diagnosis of
ARVD/C categorized as the major and minor criteria,
based on the identification of structural abnormalities,
fatty or fibrofatty replacement of RV myocardium,
electrocardiographic changes, arrhythmias of RV
origin, and familial disease66. The diagnosis is fulfilled
in the presence of two major criteria or one major
plus two minor criteria or four minor from different
groups66. Not all patients’ family members fulfilled
diagnostic criteria67,68.
A modified diagnostic criteria has been proposed
to screen and identify the family members of the
probands, who were either asymptomatic or exhibited
mild symptoms69.
ECG: The ECG in ARVD/C patients usually show a
regular sinus rhythm, with a QRS duration of greater
than 110 milliseconds in lead V1 and an inversion
of T waves in precordial leads V1-V3. The extent
of T wave inversion in the precordial leads beyond
lead V1 correlates with the extent of right ventricular
involvement70. Prolongation of QRS duration in the
right precordial leads reflects late conduction in right
ventricle68. Small electrical potentials occurring at the
end or immediately after the QRS complex in leads V1 or
V2, called ε (epsilon) waves are present in approximately
30 per cent of ARVD/C patients who have VT. ε waves
reflect delayed depolarization in the right ventricle71.
All the patients showed repolarization abnormalities
in 12 lead ECG and a T wave inversion in the leads V1
through V2, V3, V4 or V5 with complete or incomplete
right bundle branch block (RBBB). Epsilon waves
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INDIAN J MED RES, january 2010
were observed in the probands carrying the mutation in
the genes coding for the desmosomal proteins but not
in the patients with TGFβ-3 gene mutation72.
Signal averaged ECG (SAECG): Signal-averaged ECG
has shown a significant correlation between presence
of late potentials and occurrence of sustained VT73,74.
Ventricular late potentials appear to arise from the
areas of structurally abnormal myocardium in which
ventricular activation is delayed and asynchronous.
Delayed fragmented electrical activity is probably
related to re-entry of ventricular arrhythmias. Late
potentials in SAECG are observed in all the probands
irrespective of the type of ARVD/C.
Ventricular arrhythmias: The peculiar histopathology
of the disease predisposes the patient to malignant
ventricular arrhythmias75,76. VT is generally believed
to be re-entrant and is usually accompanied by
abnormalities of ventricular activation77. The presence
of zones of altered myocardium, characterized by
fibrofatty infiltration, can create re-entry circuits
representing the substrate for repetitive ventricular
arrhythmias. Ventricular tachycardia (VT) and
ventricular fibrillation (VF) are documented causes of
sudden death in ARVD/C78.
In all the ARVD/C patients irrespective of the
type, left bundle branch block (LBBB) type VT is
documented (either sustained or non sustained or both).
Probands with TGFβ-3 gene mutation presented only
non sustained ventricular tachycardia/ arrhythmias
while probands carrying the mutation in the either
desmoplakin or plakophilin-2 genes presented with
all the four types – sustained ventricular tachycardia,
non sustained VT (NVST), polymorphic ventricular
complexes (PVCs) and ventricular fibrillation.
Echocardiographic studies:
Moderate to severe dilation of RV with RV wall
motion abnormalities are observed in all ARVD/C
patients. LV involvement with LV kinetic abnormalities
of diffuse and localized forms were observed in all
the probands except in the patients with TGFβ-3 gene
mutation, in whom there was no LV involvement72.
Familial studies:
All ARVD/C patients carrying mutations in different
genes (TGFβ-3, DSP, PKP-2, DSG 2 and DSC-2) had
positive family history. Not all family members of the
probands fulfilled the diagnostic criteria but fulfilled
the modified diagnostic criteria69 though they carried
the mutation.
Histopathological findings (autopsy/biopsy):
RV dilation was observed along with extensive
replacement type fibrosis and fatty infiltration.
Surviving myocytes entrapped within fibrous and fatty
tissue showed degenerative changes and abnormal
nuclei. ARVD/C is one of the major causes of sudden
death and has variable penetrance and expressitivity.
Although genotypically family members of the patient
carry the mutant allele, phenotyically they might be
asymptomatic. As the disease progresses, they might
get symptomatic or may manifest sudden death. Hence
genetic testing would aid in identifying the mutation
carriers and help in treatment and prognosis.
Conclusions
Based on the symptoms, clinical investigations
and the probable molecular mechanisms implicated,
the three conditions, viz., Uhl’s anomaly, ARVD/C
and RVOT VT may be considered as separate clinical
entities. Different ARVD/C types can be differentiated
to an extent based on the clinical symptoms.
Mutations in the two non desmosomal genes,
cardiac RYR-2 and TGF β-3 implicated in ARVD/C-2
and ARVD/C-1 exhibit different clinical presentations
which are easily distinguishable from the symptoms and
clinical manifestations exhibited by the desmosomal
gene mutations. But in a study, two patients harbouring
the same mutation in PKP-2 gene (almost same age, the
only difference is the gender of the patients, unpublished
data) exhibited different clinical phenotypes further
complicating the condition to understand and
differentiate. Can gender be another parameter that
could affect the severity of the condition, has to be
considered. The reports on monozygotic twins suggest
the role of environmental factors on the expression of
the disease79. The identification of different types of
ARVD/Cs based on specific symptoms would aid in
genotype-phenotype correlations.
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Reprint requests: Dr Pratibha Nallari, Professor, Department of Genetics, Osmania University, Hyderabad 500 007, India
e-mail: [email protected].